Progenitor neighborhoods function as transient niches to sustain olfactory neurogenesis

Olfactory neurogenesis occurs throughout the lives of vertebrates, including in humans, and relies on the continuous differentiation and integration of neurons into a complex network. How progenitor cells convert fluctuations in cell-cell signaling into streamlined fate decisions over both space and time is poorly understood. Here, we track multicellular dynamics in the zebrafish olfactory epithelium, undertake targeted perturbations, and find that neurogenesis is driven by mutual antagonism between Notch signaling and insulinoma-associated 1a (Insm1a) that is responsive to inter-organ retinoic acid signaling. Single-cell analysis reveals that olfactory neurons emerge from transient groups of cells termed cellular neighborhoods. Stochastic modeling shows that neighborhood self-assembly is maintained by a tightly regulated bistable toggle switch. Differentiating cells migrate apically in response to brain-derived neurotrophic factor (BDNF) to take up residence as mature sensory neurons. Cumulatively, these findings reveal how stochastic signaling networks spatiotemporally regulate a balance between progenitors and derivatives, driving sustained neurogenesis in an intricate organ system.